Role of IL-17-secreting T cells in anti-viral immunity

描述：本申请将评估分泌促炎细胞因子IL-17的T细胞在病毒感染中的作用。产生IL-17的T细胞可以起到保护免受感染的作用，或者可以介导炎症和免疫病理学。已知IFN促进Th 1/Tc 1细胞的发育，同时其抑制产生IL-17的T细胞的形成。 将研究牛痘病毒模型。假设牛痘病毒可能促进产生IL-17的T细胞的产生，因为：（1）牛痘病毒驱动产生对产生IL-17的T细胞分化重要的细胞因子（IL-6、TGF β 1、TNF α）;和（2）牛痘病毒编码阻断IFN作用的免疫调节蛋白（其抑制产生IL-17的T细胞的产生）。提出了两个具体目标： (1)定义有助于产生IL-17的T细胞分化和这些细胞产生特定细胞因子的转录因子。将采用来自信号转导子和转录激活子（STAT 3）、STAT 4或T-bet缺陷的小鼠的细胞的组合以及在培养物中用不同细胞因子处理。 (2)目的研究痘苗病毒感染小鼠体内产生IL-17的T细胞的功能，观察产生IL-17的T细胞发育异常的缺陷小鼠，过继转移产生IL-17的T细胞的效果以及抗血清对IL-17的中和作用。 这些研究可能有助于开发改进的牛痘病毒疫苗，这些疫苗可以调节产生IL-17的T细胞的形成，并减少天花疫苗引起的破坏性炎症。这些研究将确定产生IL-17的T细胞在病毒感染中的作用。

Description: This application will evaluate the role of T cell secreting the pro-inflammatory cytokine IL-17 in virus infections. The IL-17-producing T cells may function to protect from infection or may mediate inflammation and immunopathology. IFN is known to promote the development of Th1/Tc1 cells while it inhibits the formation of IL-17 producing T cells. The vaccinia virus model will be investigated. The hypothesis is that vaccinia virus may promote the generation of IL-17-producing T cells because: (1) vaccinia virus drives the production of cytokines important for the differentiation of IL-17-producing T cells (IL-6, TGFbeta1, TNFalpha); and (2) vaccinia virus encodes immunomodulatory proteins that block IFN action (which inhibits the generation of IL-17-producing T cells). Two specific aims are proposed: (1) Define the transcription factors that contribute to the differentiation of IL-17-producting T cells and the production of specific cytokines by these cells. Combination of cells from mice deficient in signal transducer and activator of transcription (STAT3), STAT4 or T-bet and the treatment in culture with different cytokines will be employed. (2) To investigate the function of IL-17-producing T cells in mice infected with vaccinia virus, characterizing deficient mice with altered development of IL-17-producing T cells, the effect of adoptive transfer of IL-17-producing cells and the neutralization of IL-17 with antiserum. These studies may help the development of improved vaccinia virus vaccines which may regulate the formation of IL-17-producing T cells and reduce the damaging inflammation caused by the smallpox vaccine. These investigations will define the role of IL-17-producing T cells in virus infections.